T-type calcium channel blocker

ABSTRACT

There is provided a T-type calcium channel blocker that is optically active 1,4-dihydropyridine compound, a pharmaceutically acceptable salt thereof or a solvate thereof, of formula (1) 
                         
wherein R 1  and R 2  are independently of each other C 1-6  alkyl group or R 1  and R 2  together form —CR 5 R 6 —CR 7 R 8 , —CR 5 R 6 —CR 7 R 8 —CR 9 R 10 — or —CR 5 R 6 —CR 7 R 8 —CR 9 R 10 —CR 11 R 12 —, etc., X 1  and X 2  are independently of each other O or NR 13 , Ar is optionally substituted phenyl group, etc., R a  and R b  are independently of each other C 1-6 alkyl group, —L 2 —NR 16 R 17 , CH 2 O—L 2 —NR 16 R 17 CN, —L 2 —N(CH 2 CH 2 ) 2 NR 16  or NR 16 R 17 , etc., Y is C 1-20  alkyl group, —L 3 —NR 18 R 19   
                         
and * is absolute configuration of R.

TECHNICAL FIELD

The present invention relates to T-type calcium channel blockers beingoptically active dihydropyridine-5-phosphonate derivatives in which theabsolute configuration of 4-position on dihydropyridine ring isR-configuration. In addition, the present invention relates totherapeutic or preventive agents against diseases for which T-typecalcium channel blockers are effective.

BACKGROUND ART

It is known that dihydropyridine-5-phosphonate derivatives (racemate)show oral anti-hypertensive action to be effective for cardiovasculardiseases such as angia pectoris, cerebrovascular disease, hypertensionor the like (see, for example Patent Documents 1-7).

The above-mentioned effect is owing to vasodilation mainly based onL-type calcium channel blocking action, and similar to that of L-typecalcium antagonists represented by other numeral 1,4-dihydropyridinederivatives.

Recently, it was found that efonidipine (racemate) being arepresentative compound of dihydropyridine-5-phosphonate derivatives hasT-type calcium channel blocking action in addition to L-type calciumchannel blocking action (see, for example, Non-patent Document 1).

It is reported that the activation of T-type calcium channelparticipates in occurrence of hypercardia (see, for example Non-patentDocument 2), heart failure (see, for example Non-patent Document 2),cardiomyopathy (see, for example Non-patent Document 3), tachyarrhythmiarepresented by atrial fibrillation (see, for example Non-patent Document4), arterial sclerosis (see, for example Non-patent Document 5), renaldisorder represented by nephritis/nephropathy (see, for exampleNon-patent Document 6), renal insufficiency (see, for example Non-patentDocument 6), inflammation and edema (see, for example Non-patentDocument 7), hyper-aldosteronism (see, for example Non-patent Document8), neurogenic pain (see, for example Non-patent Document 9), andepilepsy (see, for example Non-patent Document 10). Therefore, it isthough that T-type calcium channel blockers are effective for therapy orprevention of these diseases.

-   Patent Document 1: JP 61-30591 A (1986)-   Patent Document 2: JP 60-69089 A (1985)-   Patent Document 3: JP 1-275591 A (1989)-   Patent Document 4: JP 61-63688 A (1986)-   Patent Document 5: JP 63-233992 A (1988)-   Patent Document 6: JP 62-169795 A (1987)-   Patent Document 7: JP 62-169796 A (1987)-   Non-patent Document 1: Masumiya H et al.: Eur J Pharmacol 335,p.    15-21 (1997)-   Non-patent Document 2: Mulder P et al.: J Am Coll Cardiol 29, p.    416-421 (1997)-   Non-patent Document 3: Villame J et al.: Cardiovasc Drugs Ther    15, p. 41-48 (2001)-   Non-patent Document 4: Fareh S et al.: Circulation 100, p. 2191-2197    (1999)-   Non-patent Document 5: Noll G and LuscherTF: Cardiology 89, p. 10-15    (1998)-   Non-patent Document 6: Baylis C et al.: Am J Kidney Dis 38 p.    1292-1297 (2001)-   Non-patent Document 7: Bilici D et al.: Pharmacol Res 44, p. 527-531    (2001)-   Non-patent Document 8: Lenglet S et al.: Endocrinology 143, p.    1748-60 (2002)-   Non-patent Document 9: McCallum J B et al.: Anesthesiology 98, p.    209-216 (2003)-   Non-patent Document 10: Porcello D M et al.: J Neurophysiol 89, p.    177-185 (2003)

However, dihydropyridine-5-phosphonate derivatives represented byefonidipine (racemate) have a possibility that the influence thereby onvasodilation and cardiac function based on L-type calcium channelblocking action becomes hindrance factors in the therapy of theabove-mentioned diseases. In addition, they are liable to cause loweringin Quality of Life, such as headache, flash, dizziness, edema or thelike based on vasodilation.

From the above, it is considered very useful to find T-type calciumchannel blockers having a weak or little L-type calcium channel blockingaction.

The present inventors eagerly investigated in order to solve theabove-mentioned problems. As a result of it, they found that opticallyactive dihydropyridine-5-phosphonate derivatives in which the absoluteconfiguration of 4-position on dihydropyridine ring is R-configurationshow a weak or little L-type calcium channel blocking action, and aselective blocking action against T-type calcium channel, and theycompleted the present invention.

DISCLOSURE OF INVENTION

That is, the present invention provides the followings:

1. A T-type calcium channel blocker that is optically active1,4-dihydropyridine compound, a pharmaceutically acceptable salt thereofor a solvate thereof, of formula (1)

[whereinR¹ and R² are independently of each other C₁₋₆ alkyl group {the C₁₋₆alkyl group may be substituted with phenyl group (the phenyl group maybe substituted with C₁₋₆ alkoxy group or halogen atom), C₂₋₆ alkenylgroup or C₂₋₆ alkynyl group (the C₂₋₆ alkenyl group and C₂₋₆ alkynylgroup may be substituted with phenyl group (the phenyl group may besubstituted with C₁₋₆ alkoxy group or halogen atom))}, or —L¹—NR³R⁴ {R³and R⁴ are independently of each other C₁₋₆ alkyl group (the C₁₋₆ alkylgroup may be substituted with phenyl group (the phenyl group may besubstituted with C₁₋₆ alkoxy group or halogen atom)) or phenyl group(wherein the phenyl group may be substituted with C₁₋₆ alkoxy group orhalogen atom), L¹ is C₂₋₆ alkylene group (the C₂₋₆ alkylene group may besubstituted with C₁₋₃ alkyl group or phenyl group (the phenyl group maybe arbitrarily substituted with halogen atom, C₁₋₃ alkyl group or C₁₋₃alkoxy group))}, orR¹ and R² together form —CR⁵R⁶—CR⁷R⁸—, —CR⁵R⁶—CR⁷R⁸—CR⁹R¹⁰— or—CR⁵R⁶—CR⁷R⁸—CR⁹R¹⁰—CR¹¹R¹²— (R⁵ to R¹² are independently of each otherhydrogen atom or C₁₋₆ alkyl group, or any two of them together with thecarbon atom bonding them may form 5-, 6- or 7-membered ring);X¹ and X² are independently of each other O or NR¹³ (R¹³ is hydrogenatom or C₁₋₆ alkyl group);Ar is phenyl group, pyridyl group, furyl group or2,1,3-benzoxadiazol-4-yl group {the phenyl group, pyridyl group, furylgroup and 2,1,3-benzoxadiazol-4-yl group may arbitrarily substitutedwith one or two substituents selected from NO₂, CF₃, Br, Cl, F, R(R isC₁₋₂₀ alkyl group), OH, OR¹⁴ (R¹⁴ is C₁₋₆ alkyl group), OCHF₂, COOR¹⁴,NH₂, NHR¹⁴, NR¹⁴R¹⁵ (R¹⁵ is C₁₋₆ alkyl group), CONH₂, CONHR¹⁴,CONR¹⁴R¹⁵, COSR¹⁴, SR¹⁴, S(O)R¹⁴, S(O)₂R¹⁴, SO₃H, SO₃R¹⁴, SO₂NH₂,SO₂NHR¹⁴, SO₂NR¹⁴R¹⁵, CN and phenyloxy group};R^(a) and R^(b) are independently of each other C₁₋₆ alkyl group,—L²—NR¹⁶R¹⁷ {R¹⁶ and R¹⁷ are independently of each other hydrogen atom,C₁₋₆ alkyl group (the C₁₋₆ alkyl group may be substituted with phenylgroup (the phenyl group may be substituted with C₁₋₆ alkoxy group orhalogen atom)) or phenyl group (the phenyl group may be substituted withC₁₋₆ alkoxy group or halogen atom), L² is C₂₋₆ alkylene group (the C₂₋₆alkylene group may be arbitrarily substituted with C₁₋₃ alkyl group orphenyl group (the phenyl group may be arbitrarily substituted withhalogen atom, C₁₋₃ alkyl group or C₁₋₃ alkoxy group))}, CH₂O—L²—NR¹⁶R¹⁷,Ar₁ (Ar₁ is phenyl group (the phenyl group may be arbitrarilysubstituted with halogen atom, C₁₋₃ alkyl group or C₁₋₃ alkoxy group)),CH═CHAr₁, CH₂CH(OH)Ar¹, CHO, CN, CH₂OH, CHOR¹⁶, —L²—N(CH₂CH₂)₂NR¹⁶ orNR¹⁶R¹⁷;Y is C₁₋₂₀ alkyl group {the C₁₋₂₀ alkyl group may be substituted withphenyl group (the phenyl group may be substituted with C₁₋₆ alkoxy groupor halogen atom), C₂₋₆ alkenyl group or C₂₋₆ alkynyl group (the C₂₋₆alkenyl group and C₂₋₆ alkynyl group may be substituted with phenylgroup (the phenyl group may be substituted with C₁₋₆ alkoxy group orhalogen atom))}, —L³—NR¹⁶R¹⁹ {R¹⁸ and R¹⁹ are independently of eachother C₁₋₆ alkyl group (the C₁₋₆ alkyl group may be substituted withphenyl group (the phenyl group may be substituted with C₁₋₆ alkoxy groupor halogen atom)) or phenyl group (the phenyl group may be substitutedwith C₁₋₆ alkoxy group or halogen atom), L³ is C₂₋₆ alkylene group (theC₂₋₆ alkylene group may be arbitrarily substituted with C₁₋₃ alkyl groupor phenyl group (the phenyl group may be arbitrarily substituted withhalogen atom, C₁₋₃ alkyl group or C₁₋₃ alkoxy group))},

(wherein o and p are independently of each other 3 or 4, q is 1, 2 or3), and * is absolute configuration of R.];2. The T-type calcium channel blocker that is optically active1,4-dihydropyridine compound, a pharmaceutically acceptable salt thereofor a solvate thereof, as set forth in 1., wherein Y is —L³—NR¹⁸R¹⁹ {R¹⁸and R¹⁹ are independently of each other C₁₋₆ alkyl group (the C₁₋₆ alkylgroup may be substituted with phenyl group (the phenyl group may besubstituted with C₁₋₆ alkoxy group or halogen atom)) or phenyl group(the phenyl group may be substituted with C₁₋₆ alkoxy group or halogenatom), L³ is C₂₋₆ alkylene group (the C₂₋₆ alkylene group may bearbitrarily substituted with C₁₋₃ alkyl group or phenyl group (thephenyl group may be arbitrarily substituted with halogen atom, C₁₋₃alkyl group or C₁₋₃ alkoxy group))},

(wherein o and p are independently of each other 3 or 4, q is 1, 2 or3), andR^(a) is C₁₋₆ alkyl group;3. The T-type calcium channel blocker that is optically active1,4-dihydropyridine compound, a pharmaceutically acceptable salt thereofor a solvate thereof, as set forth in 2., wherein R^(b) is C₁₋₆ alkylgroup, CN or NH₂;4. The T-type calcium channel blocker that is optically active1,4-dihydropyridine compound, a pharmaceutically acceptable salt thereofor a solvate thereof, as set forth in 1., wherein Y is C₁₋₂₀ alkyl group{the C₁₋₂₀ alkyl group may be substituted with phenyl group (the phenylgroup may be substituted with C₁₋₆ alkoxy group or halogen atom), C₂₋₆alkenyl group or C₂₋₆ alkynyl group (the C₂₋₆ alkenyl group and C₂₋₆alkynyl group may be substituted with phenyl group (the phenyl group maybe substituted with C₁₋₆ alkoxy group or halogen atom))},R^(b) is —L²—NR¹⁶R¹⁷ {R¹⁶ and R¹⁷ are independently of each otherhydrogen atom, C₁₋₆ alkyl group (the C₁₋₆ alkyl group may be substitutedwith phenyl group (the phenyl group may be substituted with C₁₋₆ alkoxygroup or halogen atom)) or phenyl group (the phenyl group may besubstituted with C₁₋₆ alkoxy group or halogen atom), L² is C₂₋₆ alkylenegroup (the C₂₋₆ alkylene group may be arbitrarily substituted with C₁₋₃alkyl group or phenyl group (the phenyl group may be arbitrarilysubstituted with halogen atom, C₁₋₃ alkyl group or C₁₋₃ alkoxy group))},CH₂O—L²—NR¹⁶R¹⁷ or —L²—N(CH₂CH₂)₂NR¹⁶, andR^(a) is C₁₋₆ alkyl group;5. The T-type calcium channel blocker that is optically active1,4-dihydropyridine compound, a pharmaceutically acceptable salt thereofor a solvate thereof, as set forth in 2., 3. or 4., wherein R¹ and R²are independently of each other C₁₋₆ alkyl group {the C₁₋₆ alkyl groupmay be substituted with phenyl group (the phenyl group may besubstituted with C₁₋₆ alkoxy group or halogen atom), C₂₋₆ alkenyl groupor C₂₋₆ alkynyl group (the C₂₋₆ alkenyl group and C₂₋₆ alkynyl group maybe substituted with phenyl group (the phenyl group may be substitutedwith C₁₋₆ alkoxy group or halogen atom))}, or R¹ and R² together form—CR⁵R⁶—CR⁷R⁸—, —CR⁵R⁶—CR⁷R⁸—CR⁹R¹⁰— or —CR⁵R⁶—CR⁷R⁸—CR⁹R¹⁰—CR¹¹R¹²— (R⁵to R¹² are independently of each other hydrogen atom or C₁₋₆ alkylgroup, or any two of them together with the carbon atom bonding them mayform 5,6- or 7-membered ring);X¹ and X² are both O;6. The T-type calcium channel blocker that is optically active1,4-dihydropyridine compound, a pharmaceutically acceptable salt thereofor a solvate thereof, as set forth in 5., wherein Ar is phenyl,3-nitrophenyl, 2-nitrophenyl, 3-chlorophenyl, 2-chlorophenyl,3-methoxyphenyl, 2-methoxyphenyl, 2-trifluoromethylphenyl,24rifluoromethylphenyl or 2,3-dichlorophenyl;7. The T-type calcium channel blocker that is optically active1,4-dihydropyridine compound, a pharmaceutically acceptable salt thereofor a solvate thereof, as set forth in 6., wherein R¹ and R² togetherform —CH₂—C(CH₃)₂—CH₂—, X¹ and X² are both 0, Ar is 3-nitrophenyl, R^(a)and R^(b) are both methyl, and Y is 2-[benzyl(phenyl)amino]ethyl;8. A pharmaceutical containing the T-type calcium channel blocker as setforth in any one of 1. to 7.;9. A therapeutic or preventive agent against a disease for which T-typecalcium channel blocking action is effective, containing the T-typecalcium channel blocker as set forth in any one of 1. to 7.;10. A therapeutic or preventive agent against hypercardia, containingthe T-type calcium channel blocker as set forth in any one of 1. to 7.;11. A therapeutic or preventive agent against heart failure, containingthe T-type calcium channel blocker as set forth in any one of 1. to 7.;12. A therapeutic or preventive agent against cardiomyopathy, containingthe T-type calcium channel blocker as set forth in any one of 1. to 7.;13. A therapeutic or preventive agent against atrial fibrillation,containing the T-type calcium channel blocker as set forth in any oneof 1. to 7.;14. A therapeutic or preventive agent against tachycardia-arrhythmia,containing the T-type calcium channel blocker as set forth in any oneof 1. to 7.;15. A therapeutic or preventive agent against arterial sclerosis,containing the T-type calcium channel blocker as set forth in any oneof 1. to 7.;16. A therapeutic or preventive agent against nephritis, containing theT-type calcium channel blocker as set forth in any one of 1. to 7.;17. A therapeutic or preventive agent against nephropathy, containingthe T-type calcium channel blocker as set forth in any one of 1. to 7.;18. A therapeutic or preventive agent against renal disorder, containingthe T-type calcium channel blocker as set forth in any one of 1. to 7.;19. A therapeutic or preventive agent against renal insufficiency,containing the T-type calcium channel blocker as set forth in any oneof 1. to 7.;20. A therapeutic or preventive agent against edema, containing theT-type calcium channel blocker as set forth in any one of 1. to 7.;21. A therapeutic or preventive agent against inflammation, containingthe T-type calcium channel blocker as set forth in any one of 1. to 7.;22. A therapeutic or preventive agent against hyper-aldosteronism,containing the T-type calcium channel blocker as set forth in any oneof 1. to 7.;23. A therapeutic or preventive agent against neurogenic pain,containing the T-type calcium channel blocker as set forth in any oneof 1. to 7.; and24. A therapeutic or preventive agent against epilepsy, containing theT-type calcium channel blocker as set forth in any one of 1. to 7.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention is described in further detail.

In the meantime, “n” means normal, “i” means iso, “s” means secondary,“t” means tertiary and “c” means cyclo in this specification.

Each substituent stated in this specification is described.

Halogen atom includes fluorine atom, chlorine atom, bromine atom andiodine atom.

C₁₋₃ alkyl group may be a straight-chain alkyl group, branched alkylgroup or C₃ cycloalkyl group, and includes for example methyl group,ethyl group, n-propyl group, i-propyl group and c-propyl group, etc.

C₁₋₆alkyl group may be a straight-chain alkyl group, branched alkylgroup or C₃₋₆ cycloalkyl group, and includes for example in addition tothe above-mentioned substituents for C₁₋₃ alkyl group, n-butyl group,i-butyl group, s-butyl group, t-butyl group, c-butyl group, n-pentylgroup, 1-methyl-n-butyl group, 2-methyl-n-butyl group, 3-methyl-n-butylgroup, 1,1-dimethyl-n-propyl group, c-pentyl group, 2-methyl-c-butylgroup, n-hexyl group, 1-methyl-n-pentyl group, 2-methyl-n-pentyl group,1,1-dimethyl-n-butyl group, 1-ethyl-n-butyl group,1,1,2-trimethyl-n-propyl group, c-hexyl group, 1-methyl-c-pentyl group,1-ethyl-c-butyl group and 1,2-dimethyl-c-butyl group, etc.

C₁₋₂₀ alkyl group may be a straight-chain alkyl group, branched alkylgroup or C₃₋₂₀ cycloalkyl group, and includes for example in addition tothe above-mentioned substituents for C₁₋₆ alkyl group, n-heptyl group,2-c-pentylethyl group, n-octyl group, 2-c-hexylethyl group,3-c-pentyl-n-propyl group, n-nonyl group, 3-c-hexyl-n-propyl group,4-c-pentyl-n-butyl group, n-decyl group, 4-c-hexyl-n-butyl group,5-c-pentyl-n-pentyl group, n-undecyl group, 5-c-hexyl-n-pentyl group,6-c-pentyl-n-hexyl group, n-dodecyl group, n-tridecyl group,n-tetradecyl group, n-pentadecyl group, n-hexadecyl group, n-heptadecylgroup, n-octadecyl group, n-nonadecyl group and n-eicosyl, etc.

C₂₋₆alkenyl group includes straight-chain or branched ones, and ethenylgroup, 1-propenyl group, 2-propenyl group, 1-methyl-1-ethenyl group,1-butenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-1-propenylgroup, 2-methyl-2-propenyl group, 1-ethylethenyl group,1-methyl-1-propenyl group, 1-methyl-2-propenyl group, 1-pentenyl group,2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-n-propylethenylgroup, 1-methyl-1-butenyl group, 1-methyl-2-butenyl group,1-methyl-3-butenyl group, 2-ethyl-2-propenyl group, 2-methyl-1-butenylgroup, 2-methyl-2-butenyl group, 2-methyl-3-butenyl group,3-methyl-1-butenyl group, 3-methyl-2-butenyl group, 3-methyl-3-butenylgroup, 1,1-dimethyl-2-propenyl group, 1-1-propylethenyl group,1,2-dimethyl-1-propenyl group, 1,2-dimethyl-2-propenyl group, 1-hexenylgroup, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenylgroup, 1-methyl-1-pentenyl group, 1-methyl-2-pentenyl group,1-methyl-3-pentenyl group, 1-methyl-4-pentenyl group, 1-n-butylethenylgroup, 2-methyl-1-pentenyl group, 2-methyl-2-pentenyl group,2-methyl-3-pentenyl group, 2-methyl-4-pentenyl group,2-n-propyl-2-propenyl group, 3-methyl-1-pentenyl group,3-methyl-2-pentenyl group, 3-methyl-3-pentenyl group,3-methyl-4-pentenyl group, 3-ethyl-3-butenyl group, 4-methyl-1-pentenylgroup, 4-methyl-2-pentenyl group, 4-methyl-3-pentenyl group,4-methyl-4-pentenyl group, 1,1-dimethyl-2-butenyl group,1,1-dimethyl-3-butenyl group, 1,2-dimethyl-1-butenyl group,1,2-dimethyl-2-butenyl group, 1,2-dimethyl-3-butenyl group,1-methyl-2-ethyl-2-propenyl group, 1-s-butylethenyl group,1,3-dimethyl-1-butenyl group, 1,3-dimethyl-2-butenyl group,1,3-dimethyl-3-butenyl group, 1-1-butylethenyl group,2,2-dimethyl-3-butenyl group, 2,3-dimethyl-1-butenyl group,2,3-dimethyl-2-butenyl group, 2,3-dimethyl-3-butenyl group,2-1-propyl-2-propenyl group, 3,3-dimethyl-1-butenyl group,1-ethyl-1-butenyl group, 1-ethyl-2-butenyl group, 1-ethyl-3-butenylgroup, 1-n-propyl-1-propenyl group, 1-n-propyl-2-propenyl group,2-ethyl-1-butenyl group, 2-ethyl-2-butenyl group, 2-ethyl-3-butenylgroup, 1,1,2-trimethyl-2-propenyl group, 14-butylethenyl group,1-methyl-1-ethyl-2-propenyl group, 1-ethyl-2-methyl-1-propenyl group,1-ethyl-2-methyl-2-propenyl group, 1-1-propyl-1-propenyl group and1-1-propyl-2-propenyl group, etc.

C₂₋₆alkynyl group includes straight-chain or branched ones, and ethynylgroup, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynylgroup, 3-butynyl group, 1-methyl-2-propynyl group, 1-pentynyl group,2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 1-methyl-2-butynylgroup, 1-methyl-3-butynyl group, 2-methyl-3-butynyl group,3-methyl-1-butynyl group, 1,1-dimethyl-2-propynyl group,2-ethyl-2-propynyl group, 1-hexynyl group, 2-hexynyl group, 3-hexynylgroup, 4-hexynyl group, 5-hexynyl group, 1-methyl-2-pentynyl group,1-methyl-3-pentynyl group, 1-methyl-4-pentynyl group,2-methyl-3-pentynyl group, 2-methyl-4-pentynyl group,3-methyl-1-pentynyl group, 3-methyl-4-pentynyl group,4-methyl-1-pentynyl group, 4-methyl-2-pentynyl group,1,1-dimethyl-2-butynyl group, 1,1-dimethyl-3-butynyl group,1,2-dimethyl-3-butynyl group, 2,2-dimethyl-3-butynyl group,3,3-dimethyl-1-butynyl group, 1-ethyl-2-butynyl group, 1-ethyl-3-butynylgroup, 1-n-propyl-2-propynyl group, 2-ethyl-3-butynyl group,1-methyl-1-ethyl-2-propynyl group and 1-1-propyl-2-propynyl group, etc.

C₁₋₃ alkoxy group may be a straight-chain alkoxy group, branched alkoxygroup or C₃ cycloalkoxy group, and includes for example methoxy group,ethoxy group, n-propoxy group, i-propoxy group and c-propoxy group, etc.

C₁₋₆ alkoxy group may be a straight-chain alkoxy group, branched alkoxygroup or C₃₋₆ cycloalkoxy group, and includes for example in addition tothe above-mentioned substituents for C₁₋₃ alkoxy group, n-butoxy group,i-butoxy group, s-butoxy group, t-butoxy group, c-butoxy group,n-pentyloxy group, 1-methyl-n-butoxy group, 2-methyl-n-butoxy group,3-methyl-n-butoxy group, 1,1-dimethyl-n-propoxy group, c-pentyloxygroup, 2-methyl-c-butoxy group, n-hexyloxy group, 1-methyl-n-pentyloxygroup, 2-methyl-n-pentyloxy group, 1,1-dimethyl-n-butoxy group,1-ethyl-n-butoxy group, 1,1,2-trimethyl-n-propoxy group, c-hexyloxygroup, 1-methyl-c-pentyloxy group, 1-ethyl-c-butoxy group and1,2-dimethyl-c-butoxy group, etc.

C₂₋₆ alkylene group includes ethylene group, propylene group, butylenegroup, pentylene group and hexylene group, etc.

5-, 6- or 7-membered rings include c-pentyl, c-hexyl and c-heptyl, etc.

Preferable R¹ and R² include the followings in which the latter is morepreferable:

1. R¹ and R² together form —CR⁵R⁶—CR⁷R⁸—, —CR⁵R⁶—CR⁷R⁸—CR⁹R¹⁰— or—CR⁵R⁶—CR⁷R⁸—CR⁹R¹⁰—CR¹¹R¹²— (R⁵ to R¹² are independently of each otherhydrogen atom or C₁₋₆ alkyl group, or any two of them together with thecarbon atom bonding them may form 5-, 6- or 7-membered ring);2. R¹ and R² together form —CR⁵R⁶—CR⁷R⁸—CR⁹R¹⁰— (R⁵ to R¹⁰ areindependently of each other hydrogen atom or C₁₋₆ alkyl group);3. R¹ and R² together form —CH₂—C(CH₃)₂—CH₂— or —CHCH₃—CH₂—CHCH₃—;4. R¹ and R² are independently of each other C₁₋₆ alkyl group {the C₁₋₆alkyl group may be substituted with phenyl group (the phenyl group maybe substituted with C₁₋₆ alkoxy group or halogen atom), C₂₋₆ alkenylgroup or C₂₋₆ alkynyl group (the C₂₋₆ alkenyl group and C₂₋₆ alkynylgroup may be substituted with phenyl group (the phenyl group may besubstituted with C₁₋₆ alkoxy group or halogen atom))};5. R¹ and R² are independently of each other C₁₋₆ alkyl group;6. R¹ and R² are both methyl group.

Preferable X¹ and X² include the followings in which the latter is morepreferable:

1. X¹ and X² are both O.

Preferable Ar includes the followings:

1. Phenyl group, 4-nitrophenyl group, 3-nitrophenyl group, 2-nitrophenylgroup, 4-chlorophenyl group, 3-chlorophenyl group, 2-chlorophenyl group,4-methoxyphenyl group, 3-methoxyphenyl group, 2-methoxyphenyl group,4-trifluoromethylphenyl group, 3-trifluoromethylphenyl group,2-trifluoromethylphenyl group and 2,3-dichlorophenyl group;2. Phenyl group, 3-nitrophenyl group, 2-nitrophenyl group,3-chlorophenyl group, 2-chlorophenyl group, 3-methoxyphenyl group,2-methoxyphenyl group, 3-trifluoromethylphenyl group,2-trifluoromethylphenyl group and 2,3-dichlorophenyl group;3. Phenyl group, 3-nitrophenyl group, 2-nitrophenyl group,3-chlorophenyl group, 2-chlorophenyl group, 3-methoxyphenyl group,2-methoxyphenyl group, 3-trifluoromethylphenyl group and2-trifluoromethylphenyl group;4. Phenyl group, 3-nitrophenyl group, 2-nitrophenyl group,3-methoxyphenyl group, 2-methoxyphenyl group, 3-trifluoromethylphenylgroup and 2-trifluoromethylphenyl group.

Preferable R^(a) includes the followings:

1. C₁₋₆ alkyl group; more preferably

2. Methyl group.

Preferable R^(b) includes the followings in which the latter is morepreferable:

1. C₁₋₆ alkyl group, CN and NH₂;

2. Methyl group, CN and NH₂;

3.—L²—NR¹⁶R¹⁷ {R¹⁶ and R¹⁷ are independently of each other hydrogenatom, C₁₋₆ alkyl group (the C₁ alkyl group may be substituted withphenyl group (the phenyl group may be substituted with C₁₋₆ alkoxy groupor halogen atom)) or phenyl group (the phenyl group may be substitutedwith C₁₋₆ alkoxy group or halogen atom), L² is C₂₋₆ alkylene group (theC₂₋₆ alkylene group may be arbitrarily substituted with C₁₋₃ alkyl groupor phenyl group (the phenyl group may be arbitrarily substituted withhalogen atom, C₁₋₃ alkyl group or C₁₋₃ alkoxy group))), —CH₂O—L²—NR¹⁶R¹⁷and —L²—N(CH₂CH₂)₂NR¹⁶;4. —CH₂O—L²—NR¹⁶R¹⁷;5.—CH₂OCH₂CH₂NH₂.

Preferable Y includes the followings in which the latter is morepreferable:

1. C₁₋₂₀ alkyl group {the C₁₋₂₀ alkyl group may be substituted withphenyl group (the phenyl group may be substituted with C₁₋₆ alkoxy groupor halogen atom), C₂₋₆ alkenyl group or C₂₋₆ alkynyl group (the C₂₋₆alkenyl group and C₂₋₆ alkynyl group may be substituted with phenylgroup (the phenyl group may be substituted with C₁₋₆ alkoxy group orhalogen atom))};2. Methyl group, ethyl group, i-propyl group, i-butyl group andmethoxyethyl group;3.—L³—NR¹⁸R¹⁹ {R¹⁸ and R¹⁹ are independently of each other C₁₋₆ alkylgroup (the C₁₋₆ alkyl group may be substituted with phenyl group (thephenyl group may be substituted with C₁₋₆ alkoxy group or halogen atom))or phenyl group (the phenyl group may be substituted with C₁₋₄ alkoxygroup or halogen atom), L³ is C₂₋₆ alkylene group (the C₂₋₆ alkylenegroup may be arbitrarily substituted with C₁₋₃ alkyl group or phenylgroup (the phenyl group may be arbitrarily substituted with halogenatom, C₁₋₃ alkyl group or C₁₋₃ alkoxy group))},

(wherein o and p are independently of each other 3 or 4, q is 1, 2 or3);4.

When the optically active 1,4-dihydropyridine compound used in thepresent invention is a compound that can form a salt, thepharmaceutically acceptable salt thereof can be also used as aneffective component.

The pharmaceutically acceptable salt includes hydrochlorides,hydrobromides, sulfates, methanesulfonates, acetates, benzoates,tartrates, phosphates, lactates, maleates, fumarates, malates,gluconates, salicylates and the like.

Preferably, hydrochlorides and methanesulfonates may be mentioned.

The solvates are not specifically limited so long as they arepharmaceutically acceptable, and concretely include hydrates and asolvate with ethanol, and the like.

T-type calcium channel blockers that are optically active1,4-dihydropyridine compound, a pharmaceutically acceptable salt thereofor a solvate thereof used in the present invention, pharmaceuticalscontaining the T-type calcium channel blockers, or therapeutic agentsagainst diseases for which T-type calcium channel blocking action iseffective, can be generally administered in oral administration formssuch as tablets, capsules, powders, granules, pills, syrups and thelike, permucosal absorption preparations such as intrarectaladministration preparations, transnasal absorption preparations,transvaginal absorption preparations and the like, transpulmonaryabsorption preparations, inhalants, ophthalmic solutions, percutaneousabsorption preparations or injections. The present preparations can beadministered as a simple therapeutic agent or as a mixture with othertherapeutic agent. They may be administered as a single item but aregenerally administered in a form of pharmaceutical composition. Thesepreparations can be produced according to any conventional method byadding pharmacologically and pharmaceutically acceptable additives. Thatis, for oral preparations, additives such as excipients, lubricants,binders, disintegrators, humectants, plasticizers, coating agents andthe like can be used. Oral liquids may be in a form of aqueous or oilysuspension, solution, emulsion, syrup, elixir and the like, or beprovided as a dry syrup that is prepared with water or other appropriatesolvent prior to use. The above-mentioned liquids may containconventional additives such as suspending agents, perfumes, diluents oremusifiers. When it is administered intrarectally, it can beadministered as a suppository. The suppository may contain suitable baseingredients such as cocoa fats, lauric fats, macrogol, glycerogelatin,witepsol, sodium stearate or a mixture thereof, and optionallyemulsifiers, suspending agents, preservatives and the like. For theinjections, the followings are used: resolvents or solubilizing agents,such as distilled water for injections that can constitute aqueousdosage form or on use-dissolved type dosage form, saline, 5% glucosesolution, propylene glycol and the like, pharmaceutical ingredients suchas pH adjusters, isotonizing agents, stabilizers and the like.

When the pharmaceuticals of the present invention are administered tohuman, the dosage is determined depending on age or state of thepatient. In case where the patient is adult, oral preparations orintrarectal administration is carried out in an amount of about 0.1 mgto 1000 mg per day per body, and an injection is administered in anamount of about 0.05 mg to 500 mg per day per body. These values aremerely examples, and the dosage is determined according to the conditionof a patient.

The scene which the present invention is applied includes the scenewhich the use of the compounds having T-type calcium channel blockingactivity is expected to improve the condition of the disease.Concretely, the compounds of the present invention are effective fortherapy or prevention of hypercardia, heart failure, cardiomyopathy,tachyarrhythmia represented by atrial fibrillation, arterial sclerosis,renal disorder represented by nephritis/nephropathy, renalinsufficiency, inflammation and edema, hyper-aldosteronism, neurogenicpain, epilepsy, and the like.

The optically active 1,4-dihydropyridine compounds of formula (I) can beproduced with reference to the methods described in JP 1-113398 A(1989), JP 2-011592 A (1990), Chem. Pharm. Bull., 40(9), 2377-2381(1992) and Chem. Pharm. Bull., 40(9), 2370-2376 (1992).

The production process thereof is shown in Scheme 1.

wherein R¹, R², X¹, X², R^(a), R^(b), Ar, Y and * are defined similarlyto the above.

First of all, styryl phosphonate (2) and optically active aminocrotonicacid derivative (3) are heated in toluene under azeotropic dehydrationcondition to obtain 1,4-dihydropyridine derivative (1a).

Next, 1,4-dihydropyridine derivative (1a) is subjected to diastereomerseparation with crystallization or chromatography, etc. to obtain(1a-R), and then the (1a-R) is subjected to methoxymethylation to obtain(1b-R), or the (1a) is subjected to methoxymethylation to obtain (1b),and then the (1b) is subjected to diastereomer separation withcrystallization or chromatography, etc. to obtain (1b-R).

Then, transesterification is carried out and methoxymethyl group iseliminated with hydrogen chloride to produce optically active1,4-dihydropyridine compound of formula (1).

In addition, according to the methods described in JP 59-161392 A(1984), JP 60-69089 A (1985), JP 60-248693 A (1985), JP 60-258194 A(1985), JP 61-30591 A (1986), JP 61-37793 A (1986), JP 61-63688 A(1986), JP 61-210092 A (1986), JP 61-254569 A (1986), JP 62-169795 A(1987), JP 62-169796 A (1987), JP 62-195392 A (1987), JP 63-68591 A(1988), JP 63-233992 (1988), JP 1-113398 A (1989), JP 1-275591 A (1989),Chem. Pharm. Bull., 40(9), p. 2362-2369, (1992) and Chem. Pharm. Bull.,40(9), p. 2370-2376, (1992), racemic 1,4-dihydropyridine compound isproduced, and then optically active 1,4-dihydropyridine compound can bealso produced by separating it with HPLC by use of an optically activecolumn.

Hereinafter, the present invention is described based on examples towhich the present invention is not limited at all.

Racemic efonidipine synthesized according to the method described in JP63-233992 A (1988) was collected with HPLC through optically activeisomer separation column to obtain R-form and S-form of efonidipine(1,4-dihydro-2,6-dimethyl-5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-4-(3-ni trophenyl)-3-pyridine carboxylic acid2-[benzyl (phenyl)amino]ethylester) that was used as examples.

HPLC Collection Condition

Column: CHIRALCEL OC (manufactured by Daicel Chemical Industries, Ltd.)

Column size: 20 cmφ×50 cm

Eluent: methanol

Column temperature: room temperature

Flow rate: 760 mL/min.

In the meantime, compounds as examples other than the above-mentionedefonidipine compound were synthesized as follows:

The compounds that 5-position of dihydropyridine ring isdiethylphosphonyl (Z2) were synthesized with reference to the productionprocess described in JP 60-69089 A (1985) and JP 60-248693 A (1985).

The compounds that 5-position of dihydropyridine ring is5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl (Z1) were synthesizedwith reference to the production process described in JP 62-169795 A(1987) and Chem. Pharm. Bull., 40(9), p. 2362-2369 (1992).

The compounds that 5-position of dihydropyridine ring is4,6-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl (Z3, Z4) weresynthesized with reference to the production process described in JP63-68591 A (1988) and Chem. Pharm. Bull., 40(9), p. 2370-2376 (1992).

In addition, the following compound (1-a) was produced according to theprocess shown below.

After 8.05 g (19.3 mmol) of compound (3), 1.64 g (21.3 mmol) of ammoniumacetate and 80 ml of ethanol were mixed, the resulting mixture wasrefluxed with heating for 45 minutes. To the obtained reaction solution,7.23 g (21.3 mmol) of compound (2) was added, and the resulting mixturewas further refluxed with heating for 3 hours. After cooling, thesolvent was distilled off under a reduced pressure, and 100 ml oftoluene and 50 ml of 10% sodium carbonate aqueous solution were added,then the resulting mixture was shaken and allowed to stand and therebyseparated into phases. The organic phase was washed with 20% sodiumchloride solution, dried over magnesium sulfate (anhydrous), and thenthe solvent was distilled off under a reduced pressure. The residue waspurified with silica gel chromatography (hexane-ethyl acetate 4:1, V/Vto ethyl acetate) to obtain 6.04 g (yield 42%) of compound (4) as yellowamorphous.

(Compound (3) was produced according to the method described inEP0599220A1.) MS m/z: 738 (M⁺+1), ¹H-NMR (CDCl₃) δ (ppm): 0.87 (3H, s),1.08 (3H, s), 2.39 (3H, d), 2.42 (2H, t), 3.51-3.73 (4H, m), 3.69 (3H,s), 4.21-4.31 (2H, m), 4.56 (1H, d), 4.70 (1H, d), 4.93 (1H, d),7.17-7.49 (16H, m), 7.62 (1H, d), 8.02 (1H, d), 8.11 (1H, m).

After 500 mg (0.678 mmol) of compound (4) was dissolved in 5 ml ofmethanol, 500 mg (1.37 mmol) of 10% HCl-MeOH was added thereto and theresulting mixture was refluxed with heating for 2.5 hours. After coolingon standing, the solvent was distilled off under a reduced pressure, and20 ml of chloroform and 10 ml of 10% sodium carbonate aqueous solutionwere added, then the resulting mixture was shaken and allowed to standand thereby separated into phases. The organic phase was washed withwater, dried over magnesium sulfate (anhydrous), and then the solventwas distilled off under a reduced pressure. The residue was purifiedwith silica gel chromatography (hexane-ethyl acetate 20:1 to ethylacetate, then chloroform-methanol 5:1, V/V) to obtain 216 mg (yield 64%)of compound (1-a) as yellow oily product.

MS m/z: 495 (M⁺), ¹H-NMR (CDCl₃) δ (ppm): 0.89 (3H, s), 1.04 (3H, s),2.46 (3H, d), 3.00-3.03 (2H, m), 3.54-3.74 (4H, m), 3.68 (3H, s),4.09-4.27 (2H, m), 4.61 (1H, d), 4.66 (1H, d), 4.89 (1H, d), 7.40 (1H,dd), 7.65 (1H, d), 8.01 (1H, d), 8.10 (1H, m), 8.47 (1H, brm).

Pharmacological Test Example 1 (effect on L-type and T-type Ca (calcium)channel expressed in mammalian cells (BHK cells))

Test Method

In this test, an electrophysiological evaluation was carried out by useof BHK (baby hamster kidney) cells in which L-type Ca channel or T-typeCa channel (α_(1G)) was expressed according to the method of Wakamori Met al. (Wakamori M et al.: J Biol Chem 273, 34857-34867,1998) based onthe whole cell patch clamp method. Each Ca-ion current was measuredthrough a patch clamp amplifier as an inward current when depolarizationpulse (10 mV in L-type Ca channel, −20 mV in T-type Ca channel) wasapplied to cells maintained at a membrane potential of −80 mV. Opticallyactive R-form or S-form of efonidipine was dissolved in extracellularsolution and applied with perfusion. At 5 minutes after the application,any variation in Ca-ion current was measured. The results are shown inCa current inhibition (%) of the compound of the present invention to Cacurrent (100%) in vehicle control.

Efonidipine R-form (mean ± SE) Ca channel Concentration Number of type(μM) Inhibition (%) experiments T-type 0.1 19.4 ± 4.88 4 1 41.7 ± 5.3  610 72.7 ± 5.6  8 L-type 10 2.2 ± 3.4 4

Efonidipine S-form (mean ± SE) Ca channel Concentration Number of type(μM) Inhibition (%) experiments T-type 0.1 7.7 1 1 42.9 ± 8.4 6 10 75.6± 7.1 3 L-type 1 55.6 ± 7.1 2Results

The optically active R-form of efonidipine showedconcentration-dependent inhibition in a concentration of 0.1 μM or morefor T-type Ca channel, and did not show any inhibition for L-type Cachannel even in a concentration of 10 μM. On the other hand, the S-formshowed a strong inhibition for L-type Ca channel that is as high as55.6±7.1% in 1 μM. From these results, it was found that R-form ofefonidipine has a high selectivity for T-type Ca channel.

In addition, L-type Ca channel inhibition was shown only by oneoptically active S-form, whereas T-type Ca channel inhibition was shownby both optically active forms to equal level. This suggests that if1,4-dihydropyridine compound showing T-type Ca channel blocking effectin a form of racemate is found, the one (R-form) of the optically activeproducts will be a compound having a high selectivity for T-type Cachannel.

Pharmacological Test Example 2 (effect on T-type Ca channel expressed inmammalian cells (BHK cells))

Test Method

Similarly to the procedure of Pharmacological Test Example 1, thecompounds of formula

were measured for T-type Ca channel inhibition in a drug concentrationof 10 μM, and the results are shown in table described below.

In the meanwhile, Z1 to Z4, Y1 to Y7, B1 and A1 to A7 used in the tablemean the kind of substituents of the compounds as follows:

B1: CH₂OCH₂CH₂NH₂ A1: 3-nitropheny, A2: 3-chlorophenyl, A3:2-nitrophenyl, A4: 2-methoxyphenyl, A5: 3-methoxyphenyl, A6: phenyl, A7:3-trifluoromethylphenyl 4-position Inhibition Number of Z Ar Y R^(b)configuration Note (%) experiments Z1 A2 Y1 methyl racemate 17.8 1 Z1 A3Y1 methyl racemate 29.9 2 Z1 A4 Y1 methyl racemate 51.0 1 Z1 A5 Y1methyl racemate 38.4 3 Z1 A6 Y1 methyl racemate 38.0 2 Z2 A1 Y1 methylracemate 38.8 1 Z2 A7 Y2 methyl racemate HCl salt 49.9 3 Z1 A1 Y3 methylracemate 39.2 2 Z1 A1 Y4 methyl racemate 55.3 2 Zi A1 Y2 methyl racemate77.0 2 Z1 A1 Y5 methyl racemate 39.0 3 Z1 A1 Y6 methyl racemate 41.8 2Z3 A1 Y7 methyl racemate 2HCl salt 81.0 4 Z4 A1 Y7 methyl (−) form 65.22 Z1 A1 Y7 methyl racemate 47.3 2 Z1 A2 methyl B1 racemate 29.9 1

As the above-mentioned compounds in a form of racemate showed T-typecalcium channel inhibition, it is assumed that the one of the opticallyactive product (R-form shows no L-type calcium channel inhibition)becomes a compound showing a selective T-type calcium channelinhibition.

Preparation Example 1

Granules containing the following components were prepared.

Components Compound of formula (1) 10 mg Lactose 700 mg Cornstarch 274mg HPC-L 16 mg 1000 mgThe compound of formula (I) and lactose were passed through 60-meshsieve. Cornstarch was passed through 120-mesh sieve. These componentswere mixed in a twin-cylinder mixer. Hydroxypropylcellulose having a lowviscosity (HPC-L) was added to the mixed powders, the resulting mixturewas kneaded, granulated (extrusion granulation, bore 0.5 to 1 mm), andthen dried. The obtained dried granules were passed through a vibratingscreen (12/60 mesh) to obtain an intended granules.

Preparation Example 2

Powders for filling into capsules containing the following componentswere prepared.

Components Compound of formula (1) 10 mg Lactose 79 mg Cornstarch 10 mgMagnesium stearate 1 mg 100 mgThe compound of formula (I) and lactose were passed through 60-meshsieve. Cornstarch was passed through 120-mesh sieve. These componentswere mixed with magnesium stearate in a twin-cylinder mixer. 100 mg of10 times powders were filled into No. 5 hard gelatin capsule.

Preparation Example 3

Granules for filling into capsules containing the following componentswere prepared.

Components Compound of formula (1) 15 mg Lactose 90 mg Cornstarch 42 mgHPC-L 3 mg 150 mgThe compound of formula (I) and lactose were passed through 60-meshsieve. Cornstarch was passed through 120-mesh sieve. These componentswere mixed in a twin-cylinder mixer. Hydroxypropylcellulose having a lowviscosity (HPC-L) was added to the mixed powders, the resulting mixturewas kneaded, granulated, and then dried. The obtained dried granuleswere passed through a vibrating screen (12/60 mesh) to obtain anintended granules. 150 mg of the granules were filled into No. 4 hardgelatin capsule.

Preparation Example 4

Tablets containing the following components were prepared.

Components Compound of formula (1) 10 mg Lactose 90 mg Fine crystallinecellulose 30 mg Magnesium stearate 5 mg CMC-Na 15 mg 150 mgThe compound of formula (1), lactose, fine crystalline cellulose andCMC-Na (carboxymethylcellulose sodium salt) were passed through 60-meshsieve and mixed one another. Magnesium stearate was added to the mixedpowders to obtain mixed powders for preparation. The powders weresubjected to direct compression to obtain 150 mg of tablets.

Preparation Example 5

Intravenous preparations were prepared as follows.

Compound of formula (1) 100 mg Saturated fatty acid glyceride 1000 mlGenerally, the solution containing the above-mentioned components wasintravenously administered to a patient in a rate of 1 ml per minute.

INDUSTRIAL APPLICABILITY

As the compounds of the present invention have selective T-type calciumchannel blocking effect, it is assumed that these compounds can be usedfor therapy of hypercardia, heart failure, cardiomyopathy,tachycardia-arrhythmia represented by atrial fibrillation, arterialsclerosis, renal disorder represented by nephritis/nephropathy, renalinsufficiency, inflammation and edema, hyper-aldosteronism, neurogenicpain, or epilepsy, without adverse effect on blood pressure, cardiacfunction and Quality of Life. Therefore, the present invention canprovide therapeutic agents for the above-mentioned diseases witheffectiveness, safety and Quality of Life, and thus it is very usefulfor example in the art of medical treatment and medicine.

1. A method of treating renal injury, the method comprising:administering to a human patient in need thereof, an effective amount ofa T-type calcium channel blocker, and a pharmaceutically acceptableexcipient, wherein the T-type calcium channel blocker is an opticallyactive 1,4-dihydropyridine compound or a pharmaceutically acceptablesalt thereof, of formula (1)

wherein: R¹ and R² are independently of each other a C₁₋₆ alkyl group,or R¹ and R² together form —CR⁵R⁶—CR⁷R⁸—CR⁹R¹⁰—, wherein: R⁵ to R¹⁰ areindependently of each other a hydrogen atom or a C₁₋₆ alkyl group; X¹and X² are O; Ar is a phenyl group that is unsubstituted or issubstituted with one or two substituents selected from the groupconsisting of NO₂, CF₃, Cl, and OR¹⁴, wherein R¹⁴ is a C₁₋₆ alkyl group;R^(a) and R^(b) are independently of each other a C₁₋₆ alkyl group, orCH₂O—L²—NR¹⁶R¹⁷, wherein R¹⁶ and R¹⁷ are a hydrogen atom, and L² is aC₂₋₆ alkylene group; Y is: a C₁₋₂₀ alkyl group, —L³—NR¹⁸R¹⁹,

wherein: R¹⁸ and R¹⁹ are independently of each other a phenyl group, ora C₁₋₆ alkyl group that is unsubstituted or is substituted with a phenylgroup, L³ is a C₂₋₆ alkylene group, and q is 2 or 3; and * is anabsolute configuration of R.
 2. A method of treating hyperaldosteronism,the method comprising: administering to a human patient in need thereof,an effective amount of a T-type calcium channel blocker, and apharmaceutically acceptable excipient, wherein the T-type calciumchannel blocker is an optically active 1,4-dihydropyridine compound or apharmaceutically acceptable salt thereof, of formula (1)

wherein: R¹ and R² are independently of each other a C₁₋₆ alkyl group,or R¹ and R² together form —CR⁵R⁶—CR⁷R⁸—CR⁹R¹⁰—, wherein: R⁵ to R¹⁰ areindependently of each other a hydrogen atom or a C₁₋₆ alkyl group; X¹and X² are O; Ar is a phenyl group that is unsubstituted or issubstituted with one or two substituents selected from the groupconsisting of NO₂, CF₃, Cl, and OR¹⁴, wherein R¹⁴ is a C₁₋₆ alkyl group;R^(a) and R^(b) are independently of each other a C₁₋₆ alkyl group, orCH₂O—L²—NR¹⁶R¹⁷, wherein R¹⁶ and R¹⁷ are a hydrogen atom, and L² is aC₂₋₆ alkylene group; Y is: a C₁₋₂₀ alkyl group, —L³—NR¹⁸R¹⁹,

wherein: R¹⁸ and R¹⁹ are independently of each other a phenyl group, ora C₁₋₆ alkyl group that is unsubstituted or is substituted with a phenylgroup, L³ is a C₂₋₆ alkylene group, and q is 2 or 3; and * is anabsolute configuration of R.
 3. A method of treating neuropathic pain,the method comprising: administering to a human patient in need thereof,an effective amount of a T-type calcium channel blocker, and apharmaceutically acceptable excipient, wherein the T-type calciumchannel blocker is an optically active 1,4-dihydropyridine compound or apharmaceutically acceptable salt thereof, of formula (1)

wherein: R¹ and R² are independently of each other a C₁₋₆ alkyl group,or R¹ and R² together form —CR⁵R⁶—CR⁷R⁸—CR⁹R¹⁰—, wherein: R⁵ to R¹⁰ areindependently of each other a hydrogen atom or a C₁₋₆ alkyl group; X¹and X² are O; Ar is a phenyl group that is unsubstituted or issubstituted with one or two substituents selected from the groupconsisting of NO₂, CF₃, Cl, and OR¹⁴, wherein R¹⁴ is a C₁₋₆ alkyl group;R^(a) and R^(b) are independently of each other a C₁₋₆ alkyl group, orCH₂O—L²—NR¹⁶R¹⁷, wherein R¹⁶ and R¹⁷ are a hydrogen atom, and L² is aC₂₋₆ alkylene group; Y is: a C₁₋₂₀ alkyl group, —L³—NR¹⁸R¹⁹,

wherein: R¹⁸ and R¹⁹ are independently of each other a phenyl group, ora C₁₋₆ alkyl group that is unsubstituted or is substituted with a phenylgroup, L³ is a C₂₋₆ alkylene group, and q is 2 or 3; and * is anabsolute configuration of R.
 4. The method of claim 1, wherein Y is: aC₁₋₂₀ alkyl group, —L³—NR¹⁸R¹⁹, or


5. The method of claim 2, wherein Y is: a C₁₋₂₀ alkyl group,—L³—NR¹⁸R¹⁹, or


6. The method of claim 3, wherein Y is: a C₁₋₂₀ alkyl group,—L³—NR¹⁸R¹⁹, or